5-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno-[3,4-f]-quinolines as selective progesterone receptor modulator compounds

Abstract

The present invention is directed to compounds, pharmaceutical compositions and methods for modulating processes mediated by Progesterone Receptor. Also provided are methods of making such compounds and pharmaceutical compositions.

1 . A method of treating an individual having a condition mediated by a progesterone receptor, comprising administering to the individual a pharmaceutically effective amount of compound represented by the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, COR 5 , CO 2 R 5 , SO 2 R 5 , and CONR 5 R 6 ;  
 R 2  and R 3  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; or  
 R 2  and R 3  taken together form a cycloalkyl ring of from three to twelve carbons;  
 R 4  is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl;  
 R 5  and R 6  each is independently selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, and C 1 -C 4  haloalkyl;  
 R 7  through R 9  each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , CO 2 R 5 , CONR 5 R 6 , C 1 -C 8  alkyl C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl; R 10  through R 15  each independently is selected from the group of hydrogen, F, Cl, Br, OR 5 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 12  and R 14  taken together form a bond, when Y is CR 14 R 15 ; or  
 R 10  and R 14  taken together form a bond, when Z is CR 14 R 15 ;  
 R 16  and R 17  each independently is selected from the group of C 1 -C 4  alkyl and C 1 -C 4  haloalkyl;  
 R 18  and R 19  each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 1 -C 4  haloalkyl and C 2 -C 4  alkenyl;  
 Y and Z each independently is selected from the group of O, S, NR 6  and CR 14 R 15 ; and  
 n is 0, 1, 2, or 3;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . The method of  claim 1 , wherein the compound is selected from among: 
 9-Fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 10);    8-methoxy-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 13);    7,9-difluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 15);    7-fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 17);    7-fluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 19);    7,9-difluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 20);    7-fluoro-5-(1,3-dithio-2-cyclohexylidene)-1,2-dihydro-2,2-dimethyl-5H-chromeno-[3,4-f]quinoline (compound 21); and    7-fluoro-5-(2-cyclohexenylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 23).    
   
   
       3 . The method of  claim 1 , wherein the condition is selected from among dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas (uterine fibroids), hot flushes, mood disorders, meningiomas, hormone-dependent cancers and female osteoporosis.  
   
   
       4 . The method of  claim 1 , wherein the condition is alleviated with female hormone replacement therapy.  
   
   
       5 . The method of  claim 1 , wherein the condition is a hormone-dependent cancer.  
   
   
       6 . The method of  claim 5 , wherein the cancer is ovarian cancer, breast cancer, endometrial cancer or prostate cancer.  
   
   
       7 . A method of modulating the fertility of an individual, comprising administering to the individual a pharmaceutically effective amount of a compound represented by the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, COR 5 , CO 2 R 5 , SO 2 R 5 , and CONR 5 R 6 ;  
 R 2  and R 3  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; or  
 R 2  and R 3  taken together form a cycloalkyl ring of from three to twelve carbons;  
 R 4  is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C—C 4  alkyl, C 1 -C 4  haloalkyl, and C—C 4  heteroalkyl;  
 R 5  and R 6  each is independently selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, and C 1 -C 4  haloalkyl;  
 R 7  through R 9  each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , CO 2 R 5 , CONR 5 R 6 , C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl;  
 R 10  through R 15  each independently is selected from the group of hydrogen, F, Cl, Br, OR 5 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 12  and R 14  taken together form a bond, when Y is CR 14 R 15 ; or  
 R 10  and R 14  taken together form a bond, when Z is CR 14 R 15 ;  
 R 16  and R 17  each independently is selected from the group of C 1 -C 4  alkyl and C 1 -C 4  haloalkyl;  
 R 18  and R 19  each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 1 -C 4  haloalkyl and C 2 -C 4  alkenyl;  
 Y and Z each independently is selected from the group of O, S, NR 6  and CR 14 R 15 ; and  
 n is 0, 1, 2, or 3;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       8 . The method of  claim 7 , wherein the compound is selected from among: 
 9-Fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 10);    8-methoxy-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-j]quinoline (compound 13);    7,9-difluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 15);    7-fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 17);    7-fluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 19);    7,9-difluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 20);    7-fluoro-5-(1,3-dithio-2-cyclohexylidene)-1,2-dihydro-2,2-dimethyl-5H-chromeno-[3,4-f]quinoline (compound 21); and    7-fluoro-5-(2-cyclohexenylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 23).    
   
   
       9 . The method of  claim 7 , wherein the compound increases the fertility of an individual.  
   
   
       10 . The method of  claim 7 , wherein the compound decreases the fertility of an individual.  
   
   
       11 . The method of  claim 10 , wherein the compound is a contraceptive, a contragestational agent or an abortifacient.  
   
   
       12 . A method of treating an individual having a hormone-dependent cancer, comprising administering to the individual a pharmaceutically effective amount of a compound represented by the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, COR 5 , CO 2 R 5 , SO 2 R 5 , and CONR 5 R 6 ;  
 R 2  and R 3  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; or  
 R 2  and R 3  taken together form a cycloalkyl ring of from three to twelve carbons;  
 R 4  is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl;  
 R 5  and R 6  each is independently selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, and C 1 -C 4  haloalkyl;  
 R 7  through R 9  each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , CO 2 R 5 , CONR 5 R 6 , C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl;  
 R 10  through R 15  each independently is selected from the group of hydrogen, F, Cl, Br, OR 5 , C—C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 12  and R 14  taken together form a bond, when Y is CR 14 R 15 ; or  
 R 10  and R 14  taken together form a bond, when Z is CR 14 R 15 ;  
 R 16  and R 17  each independently is selected from the group of C 1 -C 4  alkyl and C 1 -C 4  haloalkyl;  
 R 18  and R 19  each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , C 1 -C 4  alkyl, C—C 4  heteroalkyl, C 1 -C 4  haloalkyl and C 2 -C 4  alkenyl;  
 Y and Z each independently is selected from the group of O, S, NR 6  and CR 14 R 15 ; and  
 n is 0, 1, 2, or 3;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       13 . The method of  claim 12 , wherein the compound is selected from among: 
 9-Fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 10);    8-methoxy-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 13);    7,9-difluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 15);    7-fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 17);    7-fluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 19);    7,9-difluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 20);    7-fluoro-5-(1,3-dithio-2-cyclohexylidene)-1,2-dihydro-2,2-dimethyl-5H-chromeno-[3,4-f]quinoline (compound 21); and    7-fluoro-5-(2-cyclohexenylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 23).    
   
   
       14 . The method of  claim 12 , wherein the cancer is ovarian cancer, breast cancer, endometrial cancer or prostate cancer.  
   
   
       15 . A method of modulating a progesterone receptor in an individual, comprising administering to the individual a compound represented by the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  heteroalkyl, COR 5 , CO 2 R 5 , SO 2 R 5 , and CONR 5 R 6 ;  
 R 2  and R 3  each independently is selected from the group of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; or  
 R 2  and R 3  taken together form a cycloalkyl ring of from three to twelve carbons;  
 R 4  is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl;  
 R 5  and R 6  each is independently selected from the group of hydrogen, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, and C 1 -C 4  haloalkyl;  
 R 7  through R 9  each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , CO 2 R 5 , CONR 5 R 6 , C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl;  
 R 10  through R 15  each independently is selected from the group of hydrogen, F, Cl, Br, OR 5 , C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  heteroalkyl; or  
 R 12  and R 14  taken together form a bond, when Y is CR 14 R 15 ; or  
 R 10  and R 14  taken together form a bond, when Z is CR 14 R 15 ;  
 R 16  and R 17  each independently is selected from the group of C 1 -C 4  alkyl and C 1 -C 4  haloalkyl;  
 R 18  and R 19  each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, C 1 -C 4  haloalkyl and C 2 -C 4  alkenyl;  
 Y and Z each independently is selected from the group of O, S, NR 6  and CR 14 R 15 ; and  
 n is 0, 1, 2, or 3;  
 or a pharmaceutically acceptable salt thereof, wherein  
 the amount of compound administered is effective to modulate a progesterone receptor.  
 
   
   
       16 . The method of  claim 15 , wherein the compound is selected from among: 
 9-Fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 10);    8-methoxy-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 13);    7,9-difluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 15);    7-fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline (compound 17);    7-fluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 19);    7,9-difluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 20);    7-fluoro-5-(1,3-dithio-2-cyclohexylidene)-1,2-dihydro-2,2-dimethyl-5H-chromeno-[3,4-f]quinoline (compound 21); and    7-fluoro-5-(2-cyclohexenylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]-quinoline (compound 23).    
   
   
       17 . The method of  claim 15 , wherein the modulation is activation.  
   
   
       18 . The method of  claim 17 , wherein the compound provides at least 50% maximal activation of progesterone receptor at a concentration of less than 100 nM.  
   
   
       19 . The method of  claim 17 , wherein the compound provides at least 50% maximal activation of progesterone receptor at a concentration of less than 50 nM.  
   
   
       20 . The method of  claim 17 , wherein the compound provides at least 50% maximal activation of progesterone receptor at a concentration of less than 20 nM.  
   
   
       21 . The method of  claim 17 , wherein the compound provides at least 50% maximal activation of progesterone receptor at a concentration of less than 10 nM.  
   
   
       22 . A method of female contraception, comprising administering to a subject a compound that is primarily a progesterone receptor (PR) agonist, wherein the compound also has androgen receptor (AR) modulating activity and mineralocorticoid receptor (MR) modulating activity.